Hyperlipidemia (elevated levels of LDL-C) is a well-known risk factor of cardiovascular diseases (CVD). Statins are well known and proven drugs for the lipid management of those who are at elevated risk for developing CVD events1. However, the patients who do not tolerate statin therapy, develop any cardiovascular disease despite maximal tolerated statins, or with severe hypercholesterolemia i.e familial hypercholesterolemia had limited options. Recently the Food and Drug Administration (FDA) approved medications (PCSK-9 inhibitors) which act on a novel pathway to reduce LDL-C levels in blood.
HOW DO PCSK9 INHIBITORS WORK?
PCSK-9 inhibitors (monoclonal antibodies) act on proprotein convertase subtilsin-kexin type 9 (PCSK9) and inactivate it. The PCSK9 protein has strongly inhibit recycling of the LDL receptor (LDLR). It is predominantly produced by hepatocytes, with other sites being kidneys and intestines.2,3 On the surface of liver cell, LDL binds to its receptor called LDLR. This LDL-LDLR complex is then internalized, after which the LDLR is recycled back to the cell surface up to 150 times.4 The role of PCSK9 protein is to bind the LDLR on the surface of the hepatocyte, causing internalization and degradation of the LDL receptors in the lysosomes, this process in turn reduces the number of LDL receptors on the cell surface. So, by Inhibition of PCSK9, number of available LDL receptors on the cell surface is increased and uptake of LDL?C into the cell is augmented. PCSK9 inhibition thus offers a novel therapeutic approach for the lowering of LDL-C levels.5 Currently, the only FDA?approved PCSK9 inhibitors are two human monoclonal antibodies which bind extracellular PCSK9: alirocumab6 and evolocumab.7
FDA APPROVAL OF PCSK9 INHIBITORS AND REDUCTION IN LDL-C:
Alirocumab (Praluent) was approved by FDA in 2015 for adult patients with heterozygous familial hypercholesterolemia or for patients with clinically significant atherosclerotic CVD requiring additional LDL lowering despite being on diet control and maximal tolerated statin therapy. Alirocumab’s long-term safety and efficacy was evaluated in ODYSSEY trials which include CHOICE I, CHOICE II, OLE, LONG TERM, COMBO I, COMBO II, FH I, FH II, HIGH FH, MONO, ALTERNATIVE, OPTIONS I and OPTIONS II. There was a 65% LDL-C levels reduction in a dose dependent fashion at maximal doses.8
FDA also approved Evolocumab (Repatha) in 2015 for use in adult patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, or clinical atherosclerotic CVD requiring additional lowering of LDL cholesterol despite being on a controlled diet and maximally-tolerated statin therapy. PROFICIO (Program to reduce LDL-C and cardiovascular outcomes following inhibition of PCSK9 in different populations) phase III 14 trials were designed to evaluate efficacy and long-term safety of evolocumab. Every two-week regimen reduced LDL-C levels by up to 65% as compared to approximately 50% with every 4-wk regimen.
Alirocumab (Praluent) is given in dosage of 75-150 mg every two weeks while Evolocumab (Repatha) is given in dosage of 140 mg every two weeks or 420 mg monthly
ADVERSE EFFECTS AND LIMITATIONS
The most common adverse effects observed with Alirocumab include nasopharyngitis, erythema, itchiness, swelling, pain or tenderness, influenza, urinary tract infection, diarrhea, bronchitis, myalgia, muscle spasms, sinusitis and cough. The most common adverse effects of Evolocumab include nasopharyngitis, upper respiratory tract infection, back pain and nausea. A small percentage (2.4%) of some serious cardiac adverse events were also noted which include palpitations, angina pectoris, and ventricular premature contractions.
Some common limitations of PCSK9 inhibitors are that they are very expensive, not readily available in our country and are required in injection form.
PCSK9 inhibitors are exciting and very welcome new treatment option for patients who require treatment for their elevated LDL-C levels. They have proven to be very effective in reducing LDL-C levels and in-turn reducing ASCVD events
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Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, Hammer RE, Moon YA, Horton JD. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA. 2005;102:5374–5379.
Zaid A, Roubtsova A, Essalmani R, Marcinkiewicz J, Chamberland A, Hamelin J, Tremblay M, Jacques H, Jin W, Davignon J, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology. 2008;48:646–654.
Brown MS, Anderson RG, Goldstein JL. Recycling receptors: the round-trip itinerary of migrant membrane proteins. Cell. 1983; 32:663–667.
Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014; 114:1022–1036.
sanofi-aventis U.S. LLC . Highlights of PRALUENT prescribing information. Available at: http://products.sanofi.us/praluent/praluent.pdf. Accessed November 7, 2017.
Amgen Inc . Highlights of Repatha prescribing information. Available at: http://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/repatha/repatha_pi_hcp_english.ashx. Accessed December 6, 2017.
Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, Lisbon E, Gutierrez M, Webb C, Wu R, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–1118.